Sulphamido-benzene-azo-pyrazolone



streptococci and pneumococci;

Patented Oct. 5, 1943 The presentiinventionrelates to pyrazolone derivatives, and itparticularly relates :tO azo-pyrazolone derivatives; effectiveagainst It is among the objects of thepresentzinvention to. prepare novel azo pyrazolone: derivatives :with

enhanced therapeutic.efiiciency,flwhich have improvedbacteriostatic', analgesic and antiseptic action, andwhich maybe readily excreted.

Another. object is to provid azo-pyrazolone derivatives ,which are soluble, highlyueffective upon streptococcus andv pneumococcus' organism and which do. not cause nausea, headache and vomiting.

Still further objects and advantages will appear in the more detailed description set-forthbelow, it being I understood 1 however that thismore detailed description isgivenqby way; ofpillustrationnand explanation-only, andnot by way, of

limitation, since various changes-therein may be made by those skilled in the art WithQut departing from, the scope and spiritof the present inven- -YRKR LNNR LSOLNR R Where R and R are aryl nuclei and preferably benzene or phenyl nuclei and less preferably toluyl or Xylyl nuclei; where R is preferably a heterocyclic nucleus, pyrazolone being preferred, and being much more satisfactory than thiazole, pyrimidine, uracil, pyridine or other monazine, diazine, triazine, or similar heterocyclic nuclei; where R. and R are hydrogen, alkyl, aryl, a 2- pyridine radical, a 2-thiazole radical or a pyrimidine radical; and Where Y i hydrogen, sulpho, ethoxy, methoxy, hydroxyl, or halogen, or

where Y represents H; SOaH; ethoxy; methoxy; 55

2,330,828 NZENE-LAZOf-PYRAZOLONE a i may; gt Application mama, 1941, W Serial No. 379,040 jf e "C aims; 01. zoo-1 63 therapeutic and has the structural formula hydronyl; or, halogen; R represents 2-pyridine ,radica1,;a' 2-thiazole or a pyrimidine radical.

The preferred compound of th az o-pyrazolone serieswhich has been found to be most satisfactory and efiective is: 4-sulphamido-benzene-(lazol) -1-phenyl-3-methyl-5-pyrazolone. This compound has the empirical formula C1GH15N503S Another compound which has been found to be -quiteeffective is: 4-sulphamido-benze'ne- (l-azo- 4) -1-phenyl-sulphonic acid) -3-methyl-5-pyrazolone, and has a structural formula ribs-iii ('1 Thi compound has the empirical formula times.

Preparation of 4-sulphamido-benzene-(14120-4) 1 -phenyZ-3-methyl-5-pymz lone First 17.2 grams of sulphanilamide and 20 c. c. concentrated hydrochloric acid are dissolved, with warming, if necessary in 200 c. c. of water. This solution is cooled in ice and then diluted to one liter with water. Ice is then added and the mixture cooled to 0 to 10 C.

While stirring, a solution containing 7 grams of sodium nitrite is very slowly added. Any excess nitrous acid is destroyed by adding a small quantity of sulphamic acid.

Then 17.4 grams of l-phenyl-3-methyl-5-pyrazolone are dissolved in 400 c. 0. H2O with the addition of 40 grams anhydrous sodium carbonate and cooled to 0 to 10 C. The solution of diazotized sulphanilamide prepared above is then slowly added to the cold solution of 1-pheny1-3- EXAMPLE II Preparation of the sodiumjsalt ofi sulphamidobenzene-(i-azo 4) 1 (4 phenyZ-sulphonic acid) -3-methyl-5-pyrazolone x I First 25.3 grams of 1-(4=sulph ophenyl;-)..-3-i methyl--pyrazolone are dissolved in 4000. {c..

:willbe linked together with the arseno group being at 4 position in respect to the sulphamido group. 5

The sulphamido-azo-pyrazolones of the present application avoid the toxic symptoms usually associated with sulphanilamide derivatives, and there is av marked elimination of the tendency to nausea; vomiting, headache, hematuria, due to water containing40 grams of NazCOa and cooled to 0 to 10 C. with ice. 7

The solution of diazotized sulphanilamide is thenvery slowly added to thisfsolution" while rapidly stirring. The solution is kept alkaline at alltimes and. is then-permitted to stand' for two hours. 'The sodium salt thus producedis'rnore soluble than'the compound produced. in Exam- If the sodium salt is not completely precipitated upon standing, sodium chloride is added to salt it out. The precipitate is' filtered off andwashed withsalt solution until neutral and dried. I

The compound produced according to Example II has a pH of 7.0 in 1% solution and has a melting point of above 350 C. Where in Example 11 the benzene groupattached to the one position of the pyrazolone containsv a sulpho group, this sulpho group'may be readily converted into a sulphamido group.

Instead of the pyrazolone derivatives of Examples I and 'II,"it is also possible to combine with the diazotized sulphanilamide other pyrazolone derivativess'u'ch as 1-phenyl 2.3-diriietliyl-5-pyrazolone, 1-pheny-3-carboxy-S-pyrazolone, or 1- l-sulphophenyl) -3-carboxy-5-pyrazolone.

It is also possible to treat any one of these pyrazolone derivativesor the. pyrazolone derivatives of Examples I and II with nitrous acid to form a derivative having a -NOH' group at the 4 position which then may be reduced to". form an amino group. This amino group 'may be"di"azotized and coupled with the same or a different pyrazolone derivative to give a 'sulphamido pyrazolone-azo-pyrazolone compound of great ,.Value. In some instances it may also'be desired't'o'rerenal calculi and toxic dermatoses. These sulphamido-azo-pyrazolone derivatives also have most satisfactory analgesic and antipyretic efiect. For intravenous injection the sodium salt maybe utilized with a dosage from 5 to 7 /2 grains, while the oral dose may be lagram of '15 grains at morning and 1 gram of 15 grains at night. The sulphamido-azo-pyrazolone derivative has a high bacteriostatic-and bacteriocidal action against monoanddiplo-coccus organisms. When used intravenously, :the 'sodium salt .as, for example, produced where Example II is'used at a pH of 6 to 8 and may be buffered in isotonic solutions.

Although not preferred, the sulphamido-azopyrazolone may be combined with nicotinic acid, thiamin chloride; ascorbic acid andother water soluble vitamins as well as-with methylene blue. Many other changes could be effected in the particular features of Y sulphamido-benzene-azopyrazoloneand methods of making'the same disclosed, and in specific details thereof, Without substantially departing from the invention intended to be defined. in the claims, the specific description herein merely servingto illustrate certain elements bywhich-in one-embodiment, the spirit of.the invention maybe effectuat'ed.

What is claimed is: v 1. A therapeutic agent comprising a sulphonated sulphamido-benzene-azo-pyrazolone, the benzene being unsubstituted in the 2-, 3, 5 and 6 positions.

2. Atherapeutic agent comprising a-sulphamido-benzene- (1-azo-4) -1- l-phenyl sulphonic acid) -3-methyl-5-pyrazolone," the benzene being unsubstituted in the 2; 3, 5 and 6 positions.

IRWIN I. LUBOWEL- WILLARD T. SOMERVILLE. 

